Specific inhibitors in vitamin biosynthesis. Part 9. Reactions of 7,7-dialkyl-7,8-dihydropteridines of use in the synthesis of potential inhibitors of tetrahydrofolate biosynthesis

Abstract

Reactions of 7,7-dialkyl-7,8-dihydropteridines which are of potential use in modifying substituents on the pyrazine ring to yield compounds with inhibitory activity against 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase and dihydrofolate reductase are described. These enzymes lie along the pathway leading to the coenzyme tetrahydrofolate. 6-Methyl substituents showed typical reactivity of alkyl groups α- to a pyrazine nitrogen atom and underwent exchange of protium for deuterium under acidic and basic conditions: however, they failed to undergo clean bromination or aldol condensation. Autoxidation of alkyl groups at this position provided ready access to pteridines substituted with carbonyl groups at C-6. 6-Formyl derivatives underwent Wittig-type reactions to yield 6-aralkylidene compounds that are potential inhibitors of dihydrofolate reductase. Alkylation of the anion of 2,4-diamino-7,8-dihydro-6,7,7-trimethylpteridine occurred at N-8 in low yield. The reduction of the blocked dihydropteridine system was readily accomplished using catalytic hydrogenation in a manner analogous to that used for normal pteridines.